ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.172C>T (p.Arg58Trp) (rs201725369)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254777 SCV000230495 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000178420 SCV000246418 likely pathogenic Limb-girdle muscular dystrophy, type 2L 2015-01-22 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000254777 SCV000255642 likely pathogenic not provided 2017-09-25 criteria provided, single submitter clinical testing
Center for Genetic Medicine Research,Children's National Medical Center RCV000178420 SCV000265768 likely pathogenic Limb-girdle muscular dystrophy, type 2L 2015-12-01 criteria provided, single submitter research
GeneDx RCV000254777 SCV000321403 likely pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing The R58W variant in the ANO5 gene has been reported previously, either in the homozygous state or in trans with a second pathogenic variant, in association with myopathy, muscular dystrophy, and persistent elevated creatine kinase levels (Bouquet et al., 2012; Schessl et al., 2012; Wahbi et al., 2013; Bohlega et al., 2015; Savarese et al., 2015). The R58W variant is observed in 29/276772 (0.011%) alleles in large population cohorts (Lek et al., 2016). The R58W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R58W as a likely pathogenic variant.
Invitae RCV000684805 SCV000645877 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 58 of the ANO5 protein (p.Arg58Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs201725369, ExAC 0.03%). This variant has been reported in the homozygous state or with a second ANO5 variant in individuals affected with persistent asymptomatic hyperCK-emia (PMID: 23670307, 22499103) and limb girdle muscular dystrophy (PMID: 25891276, 27854218). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in 2 siblings affected with distal myopathy (PMID: 23041008). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 197402). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000178420 SCV000803626 uncertain significance Limb-girdle muscular dystrophy, type 2L 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Muscular dystrophy, limb-girdle, type 2L, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium . PS4-Moderate => PS4 downgraded in strength to Moderate.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254777 SCV001245644 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV001254062 SCV001429972 pathogenic Miyoshi muscular dystrophy 3 2020-02-26 criteria provided, single submitter clinical testing

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